PatientID: WM06

KindredID: 12

Case: Sex Unknown, 10Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, RET, SDHA, SDHB, SDHC, SDHD, TMEM127

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: N/A - Unspecified

LegacyVariant: Given as an unspecified germline mutation

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summarized the phenotypes of the families together. Family 20 was found with an intron mutation in the VHL gene (paper reported as IVS1-38C>T which was converted to recommended HGVS notation): both members had CNS hemangioblastomas and retinal capillary hemangioblastomas.

This intron variant (IVS1-38 C>T) is unknown. The entered coordinates do not agree with the intron/exon boundaries for the selected transcript; The base at c.340 not "C". Authors were contacted and could not confirm.

An international consortium of registered patients with head and neck paragangliomas with VHL or RET gene mutations were analyzed. Eleven of the 12 patients were found to carry germline mutations in theVHL gene. Blood was used for molecular genetic analyses and the NM_000551.2 reference sequence was used. The 26 year old female proband was found to harbour the p.Ser139fs mutation of the VHL gene. She had a family history of VHL and presented with lumbar pain. CT showed a right adrenal pheochromocytoma that was removed. Two years later, she had left nephrectomy for multiple renal cell carcinoma. At age 33, she presented with a lateral cervical mass associated with Horner’s syndrome and pain in the right ear. CT showed a 6cm carotid paraganglioma that was removed and histologically confirmed. At age 42, a cerebellar hemangioblastoma was removed. As the publication only provides the p., the mutation p.Ser139fs was not able to be matched to the exact mutation.

Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. This mutation was found in 2 Croatian, VHL type 1 family members (family VHL 26). Both have hemangioblastomas of the central nervous system, one has renal cysts, and one with pancreatic cysts.

The authors report this as an AF010238.1:c.443insTCT mutation at codon 77 (insertion Ser). This does not match the associating c. and p. - NM_000551.3:c.230_231insTCT matches Cys77_Asn78insLeu., while c.231_232insTCT (p.Cys77_Asn78insSer) would give the ins Ser the authors write, however this doesn’t match the p.. Without confirmation from authors no assumption could be made.